1. Field of the Invention
This invention relates to the production by a novel chemical synthesis of particular members of the cephalosporin family of antibiotics characterized by having 2-aminomethylphenylacetamido as their 7-substituent.
2. Description of the Prior Art
7-(2-AMINOMETHYLPHENYLACETAMIDO)-3-(1-CARBOXYMETHYLTETRAZOL-5-YLTHIOMETHYL) -3-CEPHEM-4-CARBOXYLIC ACID IS A POTENT INJECTABLE CEPHALOSPORIN HAVING THE GENERIC NAME CEFORANIDE; IT HAS ALSO BEEN CALLED BL-S786 in the literature. See, for example, Gottstein et al., J. Antibiotics, 29(11), 1226-1229 (1976) and Leitner et al., Antimicrobial Agents and Chemotherapy, 10(3), 426-435 (1976) and Research Disclosure, 157, 75-76 (May, 1977). The preparation and properties of this compound have been described, for example, in the application of my colleagues filed June 11, 1976 as U.S. Ser. No. 695,231. See also Belgium 832,725 (Farmdoc 18830X).
7-(p-Aminomethylphenylacetamido)cephalosporanic acid was described in U.S. Pat. No. 3,382,241. 7-(o-, m- and p-aminomethylphenylthioacetamido)cephalosporanic acids were disclosed in U.K. Pat. No. 1,350,238 (and see U.S. Pat. Nos. 3,657,232 and 3,663,540).
7-[M-(2'-Azidoethoxy)phenylacetamido]cephalosporanic acid was hydrogenated to produce 7-[m-(2'-aminoethoxy)phenylacetamido]cephalosporanic acid in U.S. Pat. No. 3,759,905 and the 3-acetoxy group was displaced by various heterocyclic thiols. Other thiolated 7-(o-aminomethylphenylacetamido)cephalosporins were disclosed in U.S. Pat. No. 3,766,175 (which contains an extensive review of the literature) and see also U.S. Pat. Nos. 3,813,376; 3,813,391; 3,814,755; 3,823,141; U.S. 3,907,786; 3,910,899; 3,946,000; and U.S. application Ser. No. 784,885 filed Apr. 5, 1977.
Recently issued U.S. Pat. No. 4,045,438 contains claim 1 reading
A compound selected from a base of the formula ##STR1## wherein Aryl is selected from phenyl and 2-thienyl; Y is selected from hydrogen, chlorine, bromine, a straight or branched lower alkyl group of from 1 to 4 carbon atoms and a lower alkoxy group of from 1 to 4 carbon atoms with the proviso that when Aryl is 2-thienyl, Y is hydrogen; Z is selected from a bond, oxygen, sulfur and imino with proviso that when Aryl is 2-thienyl, Z is a bond; W is selected from hydrogen, methyl, amino, hydroxy, SO.sub.3 H and COOR.sub.1 wherein R.sub.1 is selected from hydrogen and 5-indanyl; n is zero, 1 or 2 with the proviso that when W is other than hydrogen or methyl and Z is other than a bond, n is not zero; R.sub.2 is selected from hydrogen, and methoxy; M is selected from hydrogen; a pharmaceutically acceptable non-toxic cation; alkanoyloxymethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight or branched; alkanoylaminomethyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight or branched and wherein the amino nitrogen atom may be substituted with an alkyl group of from 1 to 4 carbon atoms; alkoxycarbonylaminomethyl wherein the alkoxy moiety contains from 1 to 4 carbon atoms and may be straight or branched and wherein the amino nitrogen atom may be substituted with an alkyl group of from 1 to 4 carbon atoms; p-(alkanoyloxy)benzyl wherein the alkanoyl moiety contains from 1 to 5 carbon atoms and may be straight or branched; and aminoalkanoyloxymethyl wherein the alkanoyl moiety contains from 2 to 15 carbon atoms and the amino nitrogen may be mono- or di-substituted with a lower alkyl group of from 1 to 4 carbon atoms; X is hydrogen or acetoxy; and pharmaceutically acceptable salts thereof,
and claim 26 reading
A compound selected from a base of the formula: ##STR2## wherein W' is selected from hydrogen, hydroxy, amino, COOH and SO.sub.3 H; X' is hydrogen or acetoxy; and wherein the hydrogen atoms at the 6- and 7-positions are cis to one another; and pharmaceutically acceptable salts thereof,
and claim 29 reading
"A compound of claim 26 which is 3-[(acetyloxy)-methyl[-7-[[2-[4-(azidomethyl)phenyl]-2-aminoacetyl]-amino] -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and pharmaceutically acceptable salts thereof", (and see Examples 15 and 19).
All of the specific disclosure of this patent is limited to azidomethyl substituents in the para position. Various 3-thiolated analogs are disclosed, e.g. for "X" in the formulae of claims 1 and 26. No aminomethyl substituents are disclosed.
U.S. Pat. No. 3,966,710 discloses compounds in the penicillin series having a ortho-aminomethylphenyl substituent such as 6-(o-aminomethylphenylacetamido)penicillanic acid and refers to other related disclosures as in U.K. No. 1,057,029.